Optimization of intensity-modulated radiation therapy with biological objectives.

IMRT treatment planning via biological objectives gives rise to constrained nonlinear optimization problems. We consider formulations with nonlinear objectives based on the equivalent uniform dose (EUD), with bound constraints on the beamlet weights, and describe fast, flexible variants of the two-metric gradient-projection approach for solving them efficiently and in a mathematically sound manner. We conclude that an approach that calculates the Newton component of the step iteratively, by means of the conjugate-gradient algorithm and an implicit representation of the Hessian matrix, is most effective. We also present an efficient heuristic for obtaining an approximate solution with a smoother distribution of beamlet weights. The effectiveness of the methods is verified by testing on a medium-scale clinical case.

High-Resolution Laser Photoacoustic Spectroscopy of OCS in the 12 000-13 000 cm(-1) Region.

A spectrum of natural OCS has been recorded in the near-infrared region using the laser photoacoustic technique. The source is a titanium-sapphire laser pumped by an Ar(+) laser. The tunable 1.5 W beam was sent through the photoacoustic cell. This windowless longitudinal resonant cell was designed with two lambda/4 buffer volumes at both ends in order to reduce the noise and so to increase the sensitivity (alpha(min) approximately 10(-9) cm(-1)). The spectrum of OCS, at a pressure of 90 Torr, has been recorded in the regions 11 953-12 084, 12 829-12 890, and 12 998-13 001 cm(-1). In addition to the 00(0)6-00(0)0 band of (16)O(12)C(32)S recently identified by Ch. Hornberger, B. Boor, R. Stuber, W. Demtröder, S. Naïm, and A. Fayt, J. Mol. Spectrosc. 179, 237-245, 1996, new weaker bands have been observed: 04(0)5-00(0)0, 1 10(0)3-00(0)0, 10(0)6-00(0)0, 14(0)5-00(0)0, 02(0)6-00(0)0, and 01(1)6-01(1)0, and also the 00(0)6-00(0)0 band of (16)O(12)C(34)S. Effective state parameters are deduced from the band-by-band least-squares fits. The new data have also been introduced in the global analysis which takes into account the l-type resonance and the main anharmonic interactions and so allows a full understanding of the perturbations and the intensity transfers. Copyright 1999 Academic Press.

T-and B-lymphocyte subsets in patients with Dupuytren's disease. Correlations with disease severity.

Previous reports have indicated that inflammatory mechanisms may be involved in the pathogenesis of Dupuytren's disease and it has even been suggested that this condition is a T-cell mediated autoimmune disorder. We investigated peripheral blood lymphocyte subsets from 21 patients with Dupuytren's disease and compared them with ten healthy blood donors. The Dupuytren's patients had an increase in DR+ T-cells compared with healthy controls. Furthermore, patients with both palmar and plantar involvement had a higher percentage of DR+ T-cells than those with only the palm affected. The percentage of circulating CD5+ B-cells was lower in the Dupuytren's patients compared with the control group; this feature was marginally significant for the whole group of Dupuytren's patients but was strongest in the group of patients with both palmar and plantar involvement. These findings support previous suggestions that immunological mechanisms, involving activated T-cells and probably also B-cells, are involved in the pathogenesis of Dupuytren's disease.

Photoacoustic spectroscopy of C(2)H(4) with a tunable waveguide CO(2) laser.

A photoacoustic gas spectrometer using a wave-guide CO(2), laser, tunable over 500-MHz windows in 70 lines, is described. The spectrometer is used for mapping Doppler-limited spectral signatures of ethylene and for measuring pressure-broadening rates for collisions with N(2), Ar, and He. A total of 41 observed transitions are assigned to the nu(7), nu(10), and nu(4) bands of normal ethylene and to the nu(7) band of the (13)C(12)CH(4) isotopomer.

Netilmicin in the neonate: population pharmacokinetic analysis and dosing recommendations.

Netilmicin pharmacokinetics were studied in neonates of 27 to 42 weeks' gestational age and 0.8 to 5.0 kg body weight in their first 2 weeks of life by the population pharmacokinetic approach. The data were best described by a two-compartment model. Clearance depends on body weight, gestational age, and postnatal age. Volume of distribution of the central and peripheral compartments was also related to body weight. Including these patient characteristics in the population pharmacokinetic regression model resulted in a marked reduction of the unexplained interindividual variability. This enabled us to derive dosage recommendations that result in peak and average concentrations within the desired range for 95% of the neonates with gestational age above 31 weeks, thus avoiding the need for individual drug-level monitoring in a well-defined large group of patients. Only for infants with gestational age less than 31 weeks who are less than 6 days old is individual dose adjustment based on serum concentration measurements required.

Gastric cytoprotection by intracisternal interleukin-1 beta in the rat.

The effects of intracisternal (ic) injection of recombinant interleukin-1 beta (IL-1) on absolute ethanol-induced gastric necrotic lesions were studied in conscious rats. IL-1 given ic inhibited ethanol-induced gastric lesions. The cytoprotective effect was dose dependent (ED175 ng/rat), long lasting with a maximal action when given 1-3 h prior to ethanol, blocked by ic injection of a IL-1 receptor antagonist protein (IRAP), and by intraperitoneal injection of indomethacin. IL-1, injected ic, was detected in the peripheral blood. However, IL-1 serum levels were lower after IL-1 injection ic than after ip at a dose giving equal gastric protection. These data show that ic IL-1 induces long lasting gastric protection mediated by interaction with IL-1 receptors and prostaglandin pathways at central and/or peripheral sites that remain to be localized.

Interleukin-1 is cytoprotective, antisecretory, stimulates PGE2 synthesis by the stomach, and retards gastric emptying.

Human recombinant interleukin 1 beta (IL-1) administered intraperitoneally to rats produced the following gastric effects: 1. It was cytoprotective, preventing gastric mucosal necrosis produced by oral administration of one ml of absolute ethanol to fasted animals. The ED50 was 1200 units/kg (110 ng per animal). IL-1 was 125 times more potent than prostaglandin E2 (on a weight basis), and 6,000 times more potent (on a molar basis). 2. The cytoprotective effect of IL-1 was blocked by indomethacin (inhibitor of prostaglandin synthesis) and by IRAP (a specific interleukin-1 receptor antagonist protein). IRAP did not inhibit cytoprotection induced by PGE2. 3. IL-1 prevented the formation of gastric erosions induced by aspirin. 4. IL-1 inhibited gastric secretion (volume, acid concentration and output), in the pylorus-ligated rat, with an ED50 of 300 units/kg (3.2 ng per animal). 5. Indomethacin and IRAP blocked the antisecretory effect of IL-1. 6. IL-1 retarded gastric emptying, an effect blocked by IRAP, but not by indomethacin. 7. IL-1 increased synthesis of prostaglandin E2 by the gastric mucosa by 111%. IL-1 is the most potent of known agents that are gastric cytoprotective, antiulcer, antisecretory, and delay gastric emptying. It appears to act mostly by stimulating the synthesis of prostaglandins by the stomach. These studies suggest that the stomach possesses IL-1 receptors. These are probably located on parietal cells (that produce acid), on prostaglandin-producing cells, on smooth muscle cells (responsible for gastric emptying), and on as yet unidentified cells involved in gastric cytoprotection. Both IL-1 and IRAP, being natural substances, may play a physiological role in the maintenance of gastric mucosal integrity, and in the regulation of acid secretion and gastric motility.

Prevention by prostaglandins of caerulein-induced pancreatitis in rats.

Acute edematous pancreatitis was produced in rats by subcutaneous administration of caerulein. Pancreas weight, pancreas histology and plasma amylase were used as endpoints to quantitate the severity of the syndrome. A caerulein dose of 10 micrograms/kg.hour produced the most severe pancreatitis, whereas at 5 micrograms/kg.hour the values were half-maximal. The pancreatic lesions were characterized by edema, formation of cytoplasmic vacuoles, leukocytic infiltration, necrosis, and with time (12-hour caerulein infusion) dilated acini. Cholecystokinin octapeptide also produced pancreatitis when given at ten times the dose required for caerulein (50 micrograms/kg.hour instead of 5 micrograms/kg.hour). Carbachol did not induce pancreatitis. Two prostaglandins, 16,16-dimethyl prostaglandin E2 injected subcutaneously and prostaglandin E2 infused subcutaneously, dose dependently prevented caerulein-induced pancreatitis (pancreatic edema, leukocytic infiltration, and necrosis) and reduced the number and size of intracellular vacuoles. The ED50 were 15 to 25 micrograms/kg for 16,16-dimethyl prostaglandin E2 and 90 micrograms/kg.hour for prostaglandin E2. Neither prostaglandin, given at doses inhibiting the development of pancreatitis, prevented the retardation of gastric emptying caused by caerulein, a finding suggesting that the prostaglandins may act specifically on the effect of caerulein on the pancreas but not on caerulein receptors in gastric smooth muscle. Indomethacin, an inhibitor of prostaglandin synthesis, and methscopolamine bromide, an anticholinergic agent, had no effect on caerulein-induced pancreatitis. We concluded that prostaglandins of the E type prevent the development of caerulein-induced pancreatitis. The mechanism by which prostaglandins protect the pancreas may involve stabilization of lysosomes within the acinar cells and inhibition of intracellular activation of pancreatic digestive enzymes.

The correlation between work environment and the occurrence of cervicobrachial symptoms.

The correlation between symptoms from the neck and upper extremities and some individual and work-related factors was analyzed in 2814 industrial workers. Physical stress by type of job was the factor most strongly correlated with ongoing cervicobrachial symptoms. Symptoms from the neck and upper extremities were twice as common in workers who used vibrating hand tools. Mental stress at the onset of the symptoms was associated with an increased prevalence of trapezius myalgia and with lateral humeral epicondylitis and "radial tunnel syndrome" in the dominant arm. Women had about double the rate of cervicobrachial symptoms as did men. Short stature increased the rate of symptoms from the neck, shoulders, and hands as did overweight. Playing of racquet sports decreased the risk of symptoms from the neck and hands.

Sickness absenteeism in an engineering industry--an analysis with special reference to absence for neck and upper extremity symptoms.

Neck and upper extremity symptoms (NES) are reported to increase among industrial workers. In order to quantify sickness absenteeism and relate it to some factors a questionnaire study was performed among 2,814 workers occupied at a Swedish engineering industry. Questions pertaining to age, sex, worker category, work with vibrating handtools, type of job and smoking habits were analyzed and correlated to sickness absenteeism for the previous year (1983). We found that the average days lost for personal illness was 17.2 days; 16.2 for men and 23.5 days for women. Ninety-four persons, 77 men and 17 women comprising 3.0% of all employees were sicklisted for NES corresponding to 3.3% of total sickness time lost. Blue-collar workers were sicklisted for NES five times more often than white collar workers and women in type 3 jobs (high NE stress), twice that of men occupied in the same type of job. Smokers had significantly higher absenteeism than non-smokers for any reason studied including NES. The study indicated a high prevalence of present NES problems (23%) but also that NES as a cause of leave of absence was relatively rare (3%).

Indomethacin-induced gastric antral ulcers in hamsters.

Antral ulcers account for about half of gastric ulcers in humans. An animal model was developed to produce such ulcers. Indomethacin given subcutaneously to normally fed hamsters produced antral ulcers within 1-5 h, dose dependently. These ulcers penetrated the muscularis mucosae. With repeated administration of indomethacin and longer duration of treatment, the lesions became more severe and most animals died with perforated antral ulcers after 2-5 days. Like indomethacin, aspirin given orally also produced antral ulcers in hamsters. Indomethacin reduced the formation of prostaglandin E2, prostaglandin F2 alpha, and 6-keto prostaglandin F1 alpha by the antral mucosa, and increased gastric acid output more than twofold. The ulcers were prevented by various antisecretory agents (cimetidine, methscopolamine bromide, and omeprazole), and the antiulcer dose of each of these agents corresponded to the antisecretory dose. By contrast, several prostaglandins prevented the ulcers at very low, nonantisecretory doses. 16,16-Dimethyl prostaglandin E2 prevented the ulcers at a dose nearly 3000 times lower than the gastric antisecretory ED50. The mechanism by which prostaglandins prevent formation of these ulcers is unknown, but the effect is consistent with cytoprotection, i.e., protection of the gastric mucosa by nonantisecretory doses. Indomethacin-induced antral ulcers appear to depend on two factors: a depletion of prostaglandin content of the antrum and gastric hyperacidity.

Thyroid cancer incidence in relation to volcanic activity.

Environmental or genetic factors are sought to explain the high incidence of thyroid cancer in Iceland. At present, it is impossible to cite any environmental factor, particularly one related to the volcanic activity in the country, which could explain the high incidence of thyroid cancer in Iceland. However, the thyroid gland in Icelanders is very small due to the high intake of iodine from seafood. It is, therefore, easier for physicians to find thyroid tumors. Furthermore, genetic factors are very likely to be of great importance in the small, isolated island of Iceland.

[Multifocal atrial tachycardia in the newborn infant--obstetrical implications]. / Die multifokale Vorhoftachykardie beim Neugeborenen--geburtshilfliche Implikationen.

The present discussion deals with the rare multifocal atrial tachycardia in the neonate, initiated by a recent case in our clinic. The difficulties in prenatally diagnosing the disease by cardiotocography are as well discussed as the obstetric management.

Septo-optic pituitary dysplasia. Observations on three patients.

Septo-optic pituitary dysplasia is a relatively rare but pathophysiologically interesting malformation of the brain midline structures including optic chiasm and nerves, hypothalamus, neurohypophysis and septum pellucidum. The lesion develops between the 5th and 8th week of pregnancy. The cause is unknown but heredity seems unlikely. Symptoms result from hypothalamic and neurohypophyseal insufficiency of variable severity combined with reduced vision due to hypoplasia of optic nerves and chiasm. Prognosis is variable, depending on the severity of the defect as well as on the earliest time of diagnosis followed by suitable hormone substitution and specialized care of blindness. We present the clinical course in three patients and the pathological findings in one patient who died in the 14th month of life.

Cardiomegaly in neonatal hypoglycemia.

Chest X-rays of 24 hypoglycemic newborns were compared with those of a matched control group of newborns with normal blood glucose levels. In the hypoglycemic group heart size was found to be significantly greater than in the control group. No correlation could be established between the degree of cardiomegaly and the severity of hypoglycemia. 19 of the 24 hypoglycemic children were prematures or small for dates and it is postulated that the low glycogen stores in these infants do not meet the metabolic demands of the myocardium during its postpartum circulatory adaptation.